Systemic Lupus Erythematosus (SLE) is characterized by widespread immune activation and autoantibody production, leading to vasculitis and systemic end-organ damage. The available data indicate that genes such as HLA Class II alleles and the lymphoid phosphatase PTPN22 are important risk factors for SLE, however it is likely that there are many additional alleles contributing to the SLE phenotype. During the last two years, the current application has bridged a transition into association-based studies to identify the genetic factors contributing to human lupus. In this renewal application, we propose further studies on three promising candidate genes that show evidence for association with SLE: estrogen receptor related gamma (ESRRG), PTPN22, and interferon regulatory factor 5 (IRF-5). The genetic evidence for IRF-5 is particularly strong, with our recent demonstration of an association signal in SLE that exceeds genome-wide significance (P=2.4 x 10~15). Furthermore, the SNP in IRF-5 that shows the strongest evidence for association introduces a splice donor site for an alternative first exon of the gene, leading to the production of a unique mRNA isoform and perhaps altered interferon signaling. In addition, we propose follow-up studies for the first genome-wide association screen in SLE, which is currently underway as part of the International SLE Genetics Network (SLEGEN). The current project is a collaboration between Dr. Tim Behrens, who has a long track-record of contributions to understanding the genetics and pathophysiology of SLE at the University of Minnesota, Dr. Carl Langefeld at Wake Forest University who has provided longstanding analytic support for the project, and Dr. David Altshuler at the Broad Institute of Harvard and MIT who has significant expertise in population and medical genetics. This study leverages the large, well-phenotyped Minnesota SLE family and case collection, the infrastructure for high-throughput genotyping at Broad, and significant capabilities in statistical and population genetic analysis. We anticipate that these experiments will lead rapidly to the identification of novel alleles that contribute to SLE, and ultimately to improvements in our understanding and treatment of autoimmunity. Lay summary: The current proposal aims to identify genetic factors that contribute to the autoimmune disease systemic lupus erythematosus. We expect that the information learned will lead to better ways to diagnose and treat lupus and other autoimmune diseases.